Chemotherapy in the elderly

Pers-ectiues

Chemotherapy

(A COMMEN’I‘

ON:

in the elderly: Cancer

Clin

in the Elderly

Tirelli

U, Carbonc

prospective

Oncol

studies

1987,

23,

with

A, Zagoncl

I,‘, \-croncsi

specifically

devised

A, Canctta

50%

of all cancers

arc diagnosed

this drug:

than

65 years.

rcalit),

this rquation,

be kept

in mind literature,

younger

patients,

the published Papers

This

and

when

one

and

patients

recently

have

in the literature. have

rcviewcd

ents

with

In a recent

attitudes

started report,

used

disease

is a main

Samet

diagnosed

In contrast,

ents

differ

incrcascd

from

[ 11. Several

those

prcvalencc

of distribution

body

pati-

may

potential

options

used

in younger

of associated

factors

in elderly chronic

All

these

chemotherapy may be dur cokinctics cer agents often

suffer

considerations and,

to age-related and

clearance.

pati-

changes

[2].

In addition,

from

many

chronic

relating

the

discascs,

half-life

apply

to

toxicit)-

may

Because clearance

patients,

who

take scvdelctcrious

filtration,

renal can

decreases blood

expect

cisplatin, in pharthe

area

under the plasma concentration vs. time curvr (AUC), which reflects the total exposure of the body to a drug, and the total body clcarancc of

should

influence

to intcrprct

it would

the clrarancc

the crcatininc

and

cxcretcd clearance

total

in glomcrular with

in the of the

[2].

of the

For drugs

flow occur

of two

modifications

importance

of the drug

tissue

capacity.

concurrently

directions.

as

disease),

binding

the

change

to predict

(such

renal

of‘ adipose

is under

of the

accordingly.

stantial

or chronic

be difficult

distribution

diseases

pcrcentagc

can

is potcnto two vari-

of drug

for the cffcct of a drug,

to be able dosage

thcrcforc,

and the clcarancc:

in the protein

half-life

same or in opposite

crular

dose,

the

that

an estimate

to

in

paramctcrs

of the antican-

relationships the

changes

and

of distrihution)/total

volume

failure

and by alterations

clearance

half-lifb

by associated

heart

in the pharma-

diseases,

can lead [2, 31.

One of the most important is that

elderly

The

be modified

hod).

it is related

X volume

patients:

increased

pharmacodynamics

cral medications; this drug-drug interactions macokinctics

certainly

in particular,

= (0.693

congestive

fear of increased toxicit)- of the treatment, absence of motivation and lack of social and familial support.

From

total

elimination

the volume

Since

age

the

ahlcs,

dccrcascd

why treatment

body clrarancc.

of a drug.

because

by

with

Eur~j

for the AYC

effects

misleading

1969 and 1982 and found that the proportion of potentially curative therap) cases receiving may rxplain

l>,mphomas

in 66 patients.

that

tially

PL al.

between

= dose/total it appears

determinant

half-life

to appear

in 22,899

AUC

for the biological

to appl)

practice.

therapeutic

the treatment

malignant

wants

to routine

on diagnostic

in elderly

should

when one goes through the oncowhich focuses gcncrally on

trcatmcnts

rcgimcns

535-540.)

APPROXIMATELY

1ogical

R. Non-Hodgkin’s

chcmothcrapy

in persons

older

and Commentaries

total

body

bc useful ad,just

the

by glomcan give

hod>, clearance.

Sub-

filtration

and

aging.

rate

Thcrcforc.

one

reduced clcarancc for drugs such as mcthotrexatc or blcomycin and one

USC thcsc

of the crcatininc

agents

only after

clcarancc;

a dctcrmination

this rcquircs

a reliable

urine collection which ma). not 1~ easy in the elderly. Strum crcatininr alone. which rcflccts not only crcatininc clearance but also crratininc production (which in turn reflects muscle mass and muscle turnover) may be a potentially misleading index of renal function. It is well known that a

Perspectives and Commentaries

1834 significant

and

creatinine

clearance

change

clinically

in serum

test that

capacity liver

has

a

very

hepatic

complicated

may

clearance,

but

the dosage

by the liver

arc,

How does clinical of standard doses treatment

Response older

and

studies,

the

lower

than

general some

with

severe

toxicity

of the

courses.

There

related

death.

The

overall

to elderly

as younger

of elderly these

by selection dosages

in

in

these

patients

was

patients

in the

studies

were

criteria,

that any old patient

standard

[4, 51.

However,

and

one

of chemotherapeutic

situation mized

may trial,

than

be quite

ated dose

cytosine

daunorubicin, l-3

m2/day

rate

there

leukemia

was equal

was

similar

12 early

older

lymphomas,

6-thioguanine.

to 60 mglm’lday

rcgimcn

and

in the two arms. deaths

for the patients

treated

(29 days)

for the

than

with

treated

according

on

phomas,

How-

rcgimcn the

attenuated dose regimen (150 days) (P < 0.02). The comparison of the results from these studies suggest

that,

icity of the standard parable

in

older

while dose and

the efficacy

and

chemotherapy younger

patients,

well

reduced

In

wih

27%,

the

ever,

their

use

in this

be explored

reduction

and

The

development

designed laudable lotoxin

was

arc

malignant currently

group

at

cscallym-

achieved

regimens

[lo].

that elderly patiregimens. Howof patients

appropriate

should

initial

dose

escalations.

of new

for elderly patients, goal. The regimens

regimens,

specifically

is an important and based on a podophyl-

or without

Another

important

area

of regimens

by dose

generation

are com-

tation

was

given

of myelosupprcssion

et al. fall

range. The study by Tirelli et al., recently reported in the European Journal of Cancer and Clinical Oncology [7], is important in view of the limited information

when

with

by Tirelli

intensive chemotherapy; reduced clearance leads to increased AUC and increased biological effects, which, for intensive regimens, may fall in the lethal

combination

followed

with

with

and

Although

pati-

subsequent

derivative

in the

efficacy

(CHOP)

reported

patients tolerate intensive chemotherapy poorly. Reduction in drug clearance may be one of the reasons for poor tolerance of elderly patients to

be exerted

in elderly

the toxolder

respectively.

As discussed earlier, it is unlikely cnts could tolerate these intensive perhaps

rate

survival

toxicity

results third

diffuse

prcdnisonc

patients

the so-called

with

regimens.

to the degree best

12%) respectresponse

tolerated

dosages

younger

38%

as non-Hodgkin’s

[8], the same

and

[9].

The

with

active

with

disease-free

cyclophosphamidc-doxo-

cxcessivc

in one study

53% and

should

and

with

lcukopenia-

of the antitumor of

expect

disease-free

therapeutic

combination

3

in only 3.2%

one

the complete

caution

of different

ation

in the full dosage

the full dose

patients

great

of

to 50 mg/

regimen.

dosages

was

as heterogeneous

rubicin-vincristine ents

As these

were 2 1 and

of 47 and

+

every

of 15 patients

comparison

associated

or ctoposide 5 days

by the patients.

overall

and

Formuregimens:

one should

only

rate

overall

at 3 years

In a disease

initially

arm vs. five early deaths in the attcnuatcd arm (P = 0.05) and the median survival was shorter

may

with

very

dauno-

by the dosage

1 in the attenuated

were

the

or attenuwith

and

mainly

used,

In a rando-

full dose

chemotherapy

in the full dose

response ever,

acute

either

differ

that

on day

[6].

arabinoside

two regimens

days

with

received

combination

rubicin,

different

40 patients

70 years

is being

was

at 3 years

was

the intensive chemotherapy

When

for

was observed

The

lymphomas,

toxicity

Working different

range,

response

rates

historical

can be treated

two

dose

histiocytic rates

pre-

of intermediate

i.v. weekly)

For the subgroup 53%

were

patients

to be well tolcratcd

responses.

survival

stage

for the two drugs).

regimens

ively.

to

agents.

The

orally

complete

comparable

the prevalence biased

pati-

tolerated

patients

are

of elderly

conclude

safely

Indeed, thcor-

prevalence

extent

cannot

these

patients

had

(100 mg/m2

are in the standard

lacking.

than

the majority

to the

used

(100 mg/m2

prednimustine

older

tumors

according

authors

drugs

as well

Thus,

The

Thus,

on the administration

population.

grade

lation.

lym-

patients

Forty-five 47 had

is unknown.

Data

patients.

disease.

untreated;

teniposidc to

investigated;

of the many

the older

younger

or IV

or high

capacity:

fit with these

rates

were

of non-Hodgkin

Sixty-six

weeks

at present,

survival

III

treatment

above

overall,

and

on the

in the elderly.

threshold

of chemotherapy

that,

available phomas

viously

the

experience

considerations?

ents show

and

available

be necessary

the

is reduced

to adjust

organ

metabolizing

metabolizing

drug clearance

etical

little

In addition,

large

which cleared

drug

patient.

alterations

drug

guidelines

in

very

and generally

can predict

alter

the

more

in an individual

profound

with

70 years

is no straightforward

laboratory

reduction

occur

creatinine.

The liver is a much there

important

may

into

of research

of established

prednimustine this

category.

is the efficacy

adapto the

tolerance of elderly patients. Arbitrary dose reductions and reescalations such as those used in the study with the CHOP regimen [9] constitute a very empiric way to reach this goal. It would be of great interest to be able to adapt the dose in each individual patient to his pretreatment clinical and laboratory characteristics. This will require detailed clinical and pharmacokinetic studies. Given the difficulties of clinical research in elderly patients [ 111, these studies may have to be per-

183.5

Perspectilles and Commentaries formed

first in younger

would

represent

an

patients. important

Such an approach achicvcment

elderly

for

younger

patients,

hut

would

also

brnefit

patients.

REFERENCES therapy varies with age of patient. ./ I. Samet ,J. Hunt \VC, Key C et nl. Choice of cancer .lm Meed .~lssoc 1986, 255, 3385-3390. DJ, .\hernethy DR. Shader RI. Pharmacokinetic aspects of drug therapy in 2. Greenhlatt the elderl). The Drug 12fonitoring 1986, 8, 249-255. 3. Lipschitz I);\, Goldstein S. Reis R et al. Cancer in the elderly: basic science and clinical aspects. Ann Intern .Med 1985. 102, 218-228. PP. Clinical trials and drug toxicity in the elderI>. Cnrlcer 1983. 52, 4. Begg CB. Cat-hone 198&1992. ,I. ;Ige and the treatment of multiple myeloma. .lnl ,/ .Zlfd 1985% 5. (Cohen H,J, Bartolucci 79, 3 16-324. 6 Kahn SK. Bcgg CB, Mazza .JJ, B ennett J11, Bontter H, Glick JH. Full dose \‘crsus attcnuatcd dose dauttoruhicin. cytosine arahittoside, and 6-thioguanine in (he trt‘atmettt of acute non-lymphoc\tic Icukrmia in the elderly. J C/in One-ol 1984. 2, 865-870. ;\, ‘Zagone \‘, \‘eronesi ;I, Canetta R. .Xott-Hodgkin’s 1~mphomas in 7. T‘irclli U. (:arhone the elder]!: prospective studies wih specilically devised chemotherapy regimens itt 66 patients. l:‘ur J Cancer C/in Oncol 1987. 23, 535-540. 8. :Irmitagr JO. Potter JF. Aggressive chemotherapy for diffuse histiocytic lymphoma in the eldrrly: increased complications with advanctng age. J 11m Geriatr SIC 1984, 32, 269-273. 9. Lliller 7‘1’. ,Jones SE. Initial chemotherapy for clinically localized lymphomas of unfavorBlood 1983, 62, 413-418. able histology. 11. Chemotherap) ti)r large cell Iymphotna: optimism and c.autic,n. .lw Ir~trw 10. C:olematt .\I&! 198.5, 103. l-10-142. .\\V. Calkins E. Hadley I I. Zimtncr research ilt geriatric populations.

E, Ostfeld Ann

Intern

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Ka)r Jhl, Ka)r D. Conductitlg 1985, 103, 27SL83.

clinical

to

the